Phase II Evaluation of Safety and Efficacy of MB-CART2019.1 in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Following Lymphodepletion Regimen
- Trial ID
- 2023-508508-39-01
- Protocol
- M-2018-344
- Sponsor
- Miltenyi Biomedicine GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of MB-CART2019.1 cells in subjects with relapsed and/or refractory diffuse large B cell lymphoma (R-R DLBCL) who have failed at least two lines of therapy. This will be measured by the objective response rate (ORR) based on the best overall response (BOR) following a conditioning lymphodepletion regimen. The clinical relevance of this objective lies in its potential to provide a new therapeutic option for patients with limited treatment alternatives, thereby addressing a significant unmet medical need in this patient population.
Secondary objectives include:
- Describing the outcome of subjects up to two years post-treatment, as measured by complete and objective response rates (CRR and ORR) at 1 and 6 months, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
- Evaluating the safety of MB-CART2019.1.
- Correlating the in vivo persistence of MB-CART2019.1 with clinical efficacy, incidence of cytokine release syndrome (CRS), and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).
- Characterizing the types and levels of serum cytokines associated with MB-CART2019.1 infusion.
- Evaluating immunogenicity against MB-CART2019.1.
- Exploring the relationship between antigen expression and disease progression and relapse post-treatment.
- Evaluating changes in Quality of Life (QoL) and Patient-Reported Outcome (PRO) assessments (EQ-5D-5L and FACT-Lym).
Participants
The clinical trial involves a total of **106 participants** diagnosed with **relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL)**. The study population includes both male and female subjects, aged **18 years and older**, who have failed at least two lines of therapy. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed diagnosis of DLBCL or associated subtypes, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with a status of 2 allowed if due to DLBCL. The trial population includes individuals with a measurable disease according to the Lugano 2014 criteria and those with a life expectancy of more than three months, excluding the primary disease. Participants are required to have adequate organ function, as indicated by specific laboratory values, and must be willing to practice birth control during the study. The trial does not exclude based on lifestyle factors such as diet or physical activity, but it does involve a vulnerable population, given the serious nature of the disease and prior treatment failures.
Plans and Procedures
The clinical trial is designed as a **single-arm, Phase II study** to evaluate the safety and efficacy of genetically engineered autologous cells expressing anti-CD20 and anti-CD19 specific chimeric antigen receptor in subjects with **relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL)**. The trial will involve the administration of MB-CART2019.1 cells following a conditioning lymphodepletion regimen. The primary objective is to determine the efficacy of the treatment as measured by the Objective Response Rate (ORR) based on the best overall response (BOR). The trial is expected to commence recruitment on September 1, 2024, and conclude by April 30, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histologically confirmed DLBCL, relapsed or refractory disease after two or more lines of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Following the screening, eligible participants will receive the investigational product, MB-CART2019.1, via **intravenous infusion**. The study will include follow-up visits to monitor the safety and efficacy of the treatment, with assessments conducted at 1 and 6 months post-infusion to evaluate the complete response rate (CRR) and other secondary endpoints such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
The expected length of participant involvement in the trial is approximately 42 days, with the possibility of early termination if specific conditions arise, such as adverse events or lack of efficacy. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to gather data on the long-term effects and overall outcomes of the treatment. The trial will adhere to rigorous standards to ensure the collection of high-quality data, with an independent review committee (IRC) assessing the primary endpoint using the Lugano Criteria.
Treatment
The clinical trial involves the administration of **MB-CART2019.1**, an advanced therapy medicinal product (ATMP) containing the active substance **zamtocabtagene autoleucel**. This product is administered via **intravenous infusion**. The maximum daily and total dose is 2,500,000 units/milliliter, with a treatment period of 1 day. The product is designed for use in subjects with relapsed and/or refractory diffuse large B cell lymphoma (DLBCL) following a conditioning lymphodepletion regimen.
**Buclizine hydrochloride, paracetamol, and codeine phosphate** are administered orally in a pharmaceutical form identified as PHF00082MIG. The maximum daily and total dose is 650 mg, with a treatment period of 1 day. This combination is used as an auxiliary treatment in the trial.
**Fludarabine** is administered via **intravenous infusion** in a pharmaceutical form identified as PHF675. The maximum daily dose is 30 mg/m², with a total dose of 90 mg/m² over a treatment period of 3 days. It serves as an auxiliary treatment in the study.
**Filgrastim** is administered as a solution for injection or infusion in a pharmaceutical form identified as PHF802. The maximum daily dose is 5 µg/kg, with a total dose of 70 µg/kg over a treatment period of 14 days. It is used as an auxiliary treatment in the trial.
**Allopurinol** is administered orally in a pharmaceutical form identified as PHF00005MIG. The maximum daily dose is 900 mg, with a total dose of 19.8 g over a treatment period of 22 days. It is used as an auxiliary treatment in the study.
**Bendamustine hydrochloride** is administered via **intravenous infusion** in a pharmaceutical form identified as PHF00230MIG. The maximum daily dose is 90 mg/m², with a total dose of 180 mg/m² over a treatment period of 2 days. It serves as an auxiliary treatment in the trial.
**Acalabrutinib** is administered orally in a pharmaceutical form identified as PHF00006MIG. The maximum daily dose is 200 mg, with a total dose of 8.4 g over a treatment period of 42 days. It is used as an auxiliary treatment in the study.
**Tocilizumab** is administered as a solution for infusion in a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 8 mg/kg, with a total dose of 32 mg/kg over a treatment period of 2 days. It serves as an auxiliary treatment in the trial.
**Sulfamethoxazole and trimethoprim** are administered orally in a pharmaceutical form identified as PHF00170MIG. The maximum daily dose is 1600 mg, with a total dose of 4800 mg over a treatment period of 3 days. It is used as an auxiliary treatment in the study.
**Cyclophosphamide** is administered via **intravenous infusion** in a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 300 mg/m², with a total dose of 900 mg/m² over a treatment period of 3 days. It serves as an auxiliary treatment in the trial.
**Diphenhydramine** is administered both orally and intravenously in a pharmaceutical form identified as PHF00245MIG. The maximum daily and total dose is 50 mg, with a treatment period of 1 day. It is used as an auxiliary treatment in the study.
**Levetiracetam** is administered orally in a pharmaceutical form identified as PHF00169MIG. The maximum daily dose is 1000 mg, with a total dose of 22 g over a treatment period of 22 days. It serves as an auxiliary treatment in the trial.
Efficacy
The efficacy of the investigational product MB-CART2019.1 in the treatment of **diffuse large B cell lymphoma (DLBCL)** will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the Objective Response Rate (ORR), which is defined as the proportion of subjects achieving a partial response (PR) or complete response (CR) as their best overall response. This will be evaluated using the Lugano Criteria (Cheson et al., 2014) and determined by an Independent Review Committee (IRC).
Secondary efficacy endpoints include the Complete Response Rate (CRR) at 1 and 6 months, Duration of Response (DOR), ORR at 1 and 6 months, Best Overall Response (BOR), Progression-Free Survival (PFS), and Overall Survival (OS). Additionally, the study will monitor the type, frequency, and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI). The incidence of anti-MB-CART2019.1 antibodies, phenotype and persistence of MB-CART2019.1, and the correlation of cytokine levels with the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will also be evaluated. Changes in tumor CD19 and CD20 antigen expression will be correlated with disease progression and relapse. Quality of Life (QoL) and Patient-Reported Outcome (PRO) assessments will be conducted using EQ-5D-5L and FACT-Lym instruments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification: o DLBCL not otherwise specified (NOS) o High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements o High-grade B cell lymphoma, NOS o Primary mediastinal (thymic) large B cell lymphoma o Transformed lymphoma (e.g. transformed follicular or marginal zone lymphoma, follicular lymphoma Grade 3) 1.1. CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL) 2. Relapsed or refractory disease after 2 or more lines of chemotherapy including rituximab and anthracycline and either having failed autologous stem cell transplant (ASCT), or ineligible, not intended for or not consenting to ASCT (only 2.4 applicable to CNS cohort) 2.1. Chemotherapy-refractory disease is defined as one or more of the following: • Persistent disease after last line of therapy: o Progressive disease (PD) as best response to most recent therapy regimen o Stable disease (SD) as best response to most recent therapy o Partial response (PR) with measurable lesion(s) and Deauville score of at least 4, that in the opinion of the investigator requires change of treatment to CAR-T for improvement in treatment outcome OR • Relapsed or persistent disease after prior ASCT for lymphoma o If salvage therapy is given post-ASCT, the individual must have had persistent disease (as described above) or relapsed after the last line of therapy 2.2. Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen 2.3. Not intended for ASCT is defined as meeting one of the following criteria: • Chemotherapy-refractory disease after salvage therapy • Disease progression or relapse ≤ 12 months after salvage therapy • Intolerance to salvage therapy • Age ≥ 70 2.4. CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) first-line therapy: • First-line therapy is defined as either high dose methotrexate-based therapy, temozolomide, high dose cytarabine, pemetrexed, lenalidomide or bruton thyrosine kinase (BTK) inhibitor-based therapy. • Unable to tolerate therapy is defined as Grade 3+ acute kidney injury (AKI) and/or transaminitis preventing repeat treatment exposure • Persistent disease after last line of therapy (as in 2.1) • No contraindications for MRI evaluation 2.5. CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least 1 prior line of systemic therapy • Prior lines of systemic therapy should include an anti- CD20 monoclonal antibody and anthracycline containing chemotherapy regimen and/or an autologous stem cell transplant • No contraindications for MRI evaluation In addition, all subjects must have: 3. Age ≥18 years 4. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. ECOG performance status of 2 at screen is allowed if the decrease in performance status is due to DLBCL 5. Measurable disease according to Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma (Cheson et al, 2014) for DLBCL and SCNSL while IPCG criteria for the primary PCNSL.
- Continued translation (1-5)
- CD19 or CD20 antigen expression on tumor is not required after the most recent chemoimmunotherapy; however, 6.1 Subject must have a tumor biopsy sample (at least 16 unstained slides of tissue or tissue block) from the most recent relapse available prior to MB-CART2019.1 infusion. If medically not feasible to obtain a biopsy from the most recent relapse and for cases when the amount of tissue is limited, the sponsor should be consulted, to confirm adequacy of the sample for study required analyses 6.2 If archival tissue is not available, subject must be willing to undergo attempted repeat biopsy. 7. No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort) 8. If the subject has history of CNS disease (not applicable to CNS cohort), then he/she must 8.1. Have no signs or symptoms of CNS disease 8.2. Have no active disease on magnetic resonance imaging (MRI) 8.3. Have no large cell lymphoma present in cerebral spinal fluid (CSF) on cytospin preparation and flow cytometry, regardless of the number of white blood cells (WBCs) 9. If has history of cerebral vascular accident (CVA) 9.1. The CVA event must be greater than 12 months prior to leukapheresis 9.2. Any neurological deficits must be stable 10. A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) > 60mL/min 11. Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA) 12. Resting O2 saturation >90% on room air 13. Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 times the Upper Limit of Normal (ULN) for age 14. Total bilirubin <1.5 mg/dl, except in individuals with Gilbert’s syndrome 15. Absolute neutrophil count (ANC) > 1000/μL 16. Absolute lymphocyte count > 100/μL 17. Platelet count > 50,000/μL 18. Estimated life expectancy of more than 3 months other than primary disease 19. Subjects of childbearing or childfathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study
Exclusion Criteria
- Primary CNS lymphoma (not applicable to CNS cohort) 2. Richter’s transformed DLBCL arising from chronic lymphocytic leukemia (CLL) 3. Unable to give informed consent 4. Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B (HBsAg positive). If there is a history of treated hepatitis B or hepatitis C, the viral load must be polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-HBc positive 5. Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing 6. Known history of active seizure or presence of seizure activities except CNS lymphoma related, pharmacologically controlled seizure 7. Known history of CVA within prior 12 months 8. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease 9. Presence of active CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity 9.1. For CNS Cohort: • Bulky leptomeningeal disease and or CSF protein >100 mg/Dl • Recent (within 2 months) whole brain radiotherapy (WBRT) 10. Active systemic fungal, viral or bacterial infection 11. Pregnant or breast-feeding woman 12. Previous or concurrent malignancy with the following exceptions: • Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry) • In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study • Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years • A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years 13. History of non-neurologic autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus) requiring systemic immunosuppressive or systemic disease modifying agents within the last 2 years 14. Medical condition requiring prolonged use of systemic corticosteroids equivalent to Prednisone >10 mg/day 15. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment 16. Concurrent radiotherapy (normal tissue sparing palliative radiotherapy allowed up to time of lymphodepletion). For systemic therapy, at least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed at the time of scheduled leukapheresis 17. Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline. (Appendix 6, Section 13.6) 18. History of severe immediate hypersensitivity reaction to any of the agents used in this study 19. Refusal to participate in additional lentiviral gene therapy long-term follow-up (LTFU) protocol 20. Prior CAR-T therapy for any indication or systemic gene-modifying therapy for DLBCL 21. Prior allogeneic stem cell transplant for any indication. 22. Prior Bispecific T cell engaging (BITE) antibodies for cancer therapy 23. Prior T cell receptor-engineered T cell therapy
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Croatia | Not Recruiting | 01 Sept 2024 | 2 |
 Hungary | Not Recruiting | 01 Sept 2024 | 2 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SULFAMETHOXAZOLE AND TRIMETHOPRIM | Other | PHF00170MIG | ORAL | 1600 | 3 | SCP1166649 |
ACALABRUTINIB | Other | PHF00006MIG | ORAL | 200 | 42 | SCP46660836 |
ALLOPURINOL | Other | PHF00005MIG | ORAL | 900 | 22 | SCP130703 |
BENDAMUSTINE | Other | PHF00230MIG | INTRAVENIOUS INFUSION | 90 | 2 | SCP20211730 |
LEVETIRACETAM | Other | PHF00169MIG | ORAL | 1000 | 22 | SCP1053884 |
FILGRASTIM | Other | PHF802 | SOLUTION FOR INJECTION OR INFUSION | 5 | 14 | SCP147553 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS INFUSION | 300 | 3 | SCP130444 |
MB-CART2019.1 | Test | INFUSION | INTRAVENIOUS INFUSION | 2500000 | 1 | PRD6952233 |
TOCILIZUMAB | Other | PHF00231MIG | SOLUTION FOR INFUSION | 8 | 2 | SCP176238 |
PARACETAMOL | Other | PHF00082MIG | ORAL | 650 | 1 | SCP1081917 |